Key result
ISRIB protects against doxorubicin-induced cardiotoxicity while enhancing tumor regression in murine models.
Why the study?
Anthracycline chemotherapeutics cause dose-dependent cardiotoxicity without effective preventive strategies, driven by the maladaptive ATF4-dependent integrated stress response.
Does integrated stress response (ISR) inhibition prevent doxorubicin-induced cardiotoxicity and enhance antitumor efficacy in murine models?
Does integrated stress response (ISR) inhibition prevent doxorubicin-induced cardiotoxicity and enhance antitumor efficacy in murine models?
Inhibition of the integrated stress response represents a promising therapeutic strategy to prevent anthracycline-induced cardiotoxicity while simultaneously enhancing chemotherapeutic efficacy.
ISR inhibition may confer dual cardioprotection and antitumor benefit in mice; leaves open translation to human anthracycline regimens.
The clinical efficacy of anthracycline chemotherapeutics is severely limited by their dose-dependent cardiotoxicity, a condition lacking effective preventive strategies. We identify the maladaptive ATF4-dependent integrated stress response (ISR) program as a central driver of this pathology. In murine models, ISR inhibition achieved by either cardiomyocyte-specific knockout of the transcription factor ATF4 or the ISR inhibitor (ISRIB), provides robust protection from doxorubicin (DOX)-induced cardiac dysfunction, remodeling, and injury. Mechanistically, we delineate a regulatory pathway in which DOX-activated ATF4 directly upregulates the methyltransferase METTL1. This ATF4-METTL1 axis promotes N 7 -methylguanosine (m 7 G) methylation of NLRP3 mRNA, thereby triggering NLRP3 inflammasome activation, mitochondrial damage, and cardiomyocyte pyroptosis. Crucially, pharmacological ISR inhibition with ISRIB synergizes with DOX to enhance tumor regression in xenograft models without causing cardiac injury. These findings establish the ISR as a therapeutically actionable target to simultaneously prevent anthracycline-induced cardiotoxicity and enhance chemotherapeutic efficacy, offering a promising strategy to refine cancer treatment.
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Yang et al. (2026) studied Anthracycline-induced cardiotoxicity. Integrated stress response inhibition (ATF4 knockout or ISRIB) vs. Doxorubicin alone was evaluated on Cardiac dysfunction, remodeling, and injury; tumor regression. In murine models, integrated stress response inhibition with ISRIB protected against doxorubicin-induced cardiotoxicity while synergistically enhancing tumor regression.
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